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Stille coupling of stereochemically defined α- sulfonamidoorganostannanes
Addition of tributylstannylmetallics to (R)-tert-butanesulfonimine derivatives of arylaldehydes provides α-sulfinamidostannanes with high (>98% de) diastereoselectivities. Oxidation of these compounds with m-CPBA gives α-sulfonamidostannanes which undergo Pd/Cu-catalyzed Stille-type couplings with benzoyl chloride. Best yields are achieved using the electron-rich tris(2,4,6-trimethoxyphenyl)phosphine as the ligand. Inversion of configuration at the benzylic carbon is observed. Copyright
Kells, Kevin W.,Chong, J. Michael
p. 15666 - 15667
(2004)
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Discovery of M3Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease
In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.
Armani, Elisabetta,Rizzi, Andrea,Capaldi, Carmelida,De Fanti, Renato,Delcanale, Maurizio,Villetti, Gino,Marchini, Gessica,Pisano, Anna Rita,Pitozzi, Vanessa,Pittelli, Maria Gloria,Trevisani, Marcello,Salvadori, Michela,Cenacchi, Valentina,Puccini, Paola,Amadei, Francesco,Pappani, Alice,Civelli, Maurizio,Patacchini, Riccardo,Baker-Glenn, Charles A.G.,Van De Po?l, Hervé,Blackaby, Wesley P.,Nash, Kevin,Amari, Gabriele
supporting information
p. 9100 - 9119
(2021/07/19)

Synthesis ofN-Boc-α-amino Acids from Carbon Dioxide by Electrochemical Carboxylation ofN-Boc-α-aminosulfones
Electrochemical reduction ofN-Boc-α-aminosulfones in DMF using an undivided cell equipped with a Pt plate cathode and an Mg rod anode under atmospheric pressure of bubbling carbon dioxide through the solution under constant current conditions resulted in a reductive C-S bond cleavage with elimination of benzenesulfinate ion generating the corresponding anion species followed by fixation of carbon dioxide to give the correspondingN-Boc-α-amino acids in moderate to good yields.
Senboku, Hisanori,Minemura, Yoshihito,Suzuki, Yuto,Matsuno, Hidetoshi,Takakuwa, Mayu
p. 16077 - 16083
(2021/10/12)

Anti-amyotrophic lateral sclerosis effect of thiourea homologues compound
The invention relates to an anti-amyotrophic lateral sclerosis effect of a thiourea homologues compound, and belongs to the technical field of motor neuron disease treatment. The technical problem tobe solved by the invention is that the thiourea homologues compound has the effect of resisting amyotrophic lateral sclerosis. The structure of the compound is shown as the description, and the compound has the effect of resisting amyotrophic lateral sclerosis.
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Paragraph 0007-0008

(2020/12/30)

Synthesis, characterization and antimicrobial activity of some novel 1-substituted benzimidazole derivatives
Background: Benzimidazole derivatives are an important class of heterocyclic compounds in organic chemistry as they are related to a wide range of biological properties, including antimicrobial activity. Methods: A series of 1-naphthoyl and benzoyl benzimidazole derivatives were synthesised, identified and screened for their antimicrobial activities against a number of different test organisms such as Escherichia coli, Pseudomonas aureginosa, Klebsiella pneumoniae, Staphylococcus aureus, En-terococcus faecalis, Bacillus cereus, Salmonella typhimurium, Candida albicans (yeast). Results and Discussion: Benzimidazole derivatives (3a-d) were synthesised by using 4 different aminoacids. L-methionine, L-isoleucine, D-Phenylysine and L-Phenylamine as starting materials in the study. Experimental studies involve the use of benzimidazole derivatives (3a-d) of the selected amino acids to synthesize the benzoyl and naphthoyl derivatives of benzimidazole (4a-d, 5a-c). The structures of the synthesized compounds were confirmed by spectroscopic analyses (FTIR,1H-NMR,13C-NMR) and elemental analysis. Conclusion: In this study, only one compound (5a) showed a low MIC value against the eukaryotic microorganism C. albicans. The other six compounds showed higher antimicrobial activities against the prokaryotes C. albicans which is a normal flora in the mouth but is one of the organisms that cause infections leading to the weakening of the human immune system. Compound 5a is a can-didate for future alternative antimicrobial drugs against C. albicans infections. In addition, compound 5a has a potential to be used as an inhibitor against P. aureginosa for the treatment of cyst-ic fibrosis.
Astley, Demet,Isik, Erkut,Yasa, Ihsan,Yuksekdanaci, Seda
p. 1372 - 1379
(2020/10/06)

ALLOSTERIC EGFR INHIBITORS AND METHODS OF USE THEREOF
The disclosure relates to compounds that act as an allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
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Page/Page column 62-63; 90

(2021/01/22)

A new type of L-Tertiary leucine-derived ligand: Synthesis and application in Cu(II)-catalyzed asymmetric Henry reactions
A new series of Schiff bases derived from amino acids were developed as chiral ligands for Cu(II)-catalyzed asymmetric Henry reactions. The optimum ligand 7d exhibited outstanding catalytic efficiency in the Cu(II)-catalyzed asymmetric Henry additions of four nitroalkanes to different kinds of aldehydes to produce 76 desired adducts in high yields (up to 96%) with excellent enantioselectivities, up to 99% enantiomeric excess (ee).
Cai, Zedong,Lan, Ting,Ma, Pengfei,Zhang, Jingfang,Yang, Qingqing,He, Wei
(2019/08/08)

Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment
UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, we discovered a small molecule 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86, and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, we found that 33i induced autophagy via the ULK complex in SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.
Ouyang, Liang,Zhang, Lan,Zhang, Shouyue,Yao, Dahong,Zhao, Yuqian,Wang, Guan,Fu, Leilei,Lei, Peng,Liu, Bo
supporting information
p. 2776 - 2792
(2018/04/23)

Synthesis of Tripeptide Derivatives with Three Stereogenic Centers and Chiral Recognition Probed by Tetraaza Macrocyclic Chiral Solvating Agents Derived from d -Phenylalanine and (1 S,2 S)-(+)-1,2-Diaminocyclohexane via 1H NMR Spectroscopy
Enantiomers of a series of tripeptide derivatives with three stereogenic centers (±)-G1-G9 have been prepared from d- and l-α-amino acids as guests for chiral recognition by 1H NMR spectroscopy. In the meantime, a family of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1d has been synthesized from d-phenylalanine and (1S,2S)-(+)-1,2-diaminocyclohexane. Discrimination of enantiomers of (±)-G1-G9 was carried out in the presence of TAMCSAs 1a-1d by 1H NMR spectroscopy. The results indicate that enantiomers of (±)-G1-G9 can be effectively discriminated in the presence of TAMCSAs 1a-1d by 1H NMR signals of multiple protons exhibiting nonequivalent chemical shifts (ΔΔδ) up to 0.616 ppm. Furthermore, enantiomers of (±)-G1-G9 were easily assigned by comparing 1H NMR signals of the split corresponding protons with those attributed to a single enantiomer. Different optical purities (ee up to 90%) of G1 were clearly observed and calculated in the presence of TAMCSAs 1a-1d, respectively. Intermolecular hydrogen bonding interactions were demonstrated through theoretical calculations of enantiomers of (±)-G1 with TAMCSA 1a by means of the hybrid functional theory with the standard basis sets of 3-21G of the Gaussian 03 program.
Feng, Lei,Gao, Guangpeng,Zhao, Hongmei,Zheng, Li,Wang, Yu,Stavropoulos, Pericles,Ai, Lin,Zhang, Jiaxin
p. 13874 - 13887
(2018/11/23)

Dynamic Kinetic Resolution of N-Protected Amino Acid Esters via Phase-Transfer Catalytic Base Hydrolysis
Asymmetric base hydrolysis of α-chiral esters with synthetic small-molecule catalysts is described. Quaternary ammonium salts derived from quinine were used as chiral phase-transfer catalysts to promote the base hydrolysis of N-protected amino acid hexafluoroisopropyl esters in a CHCl3/NaOH (aq) via dynamic kinetic resolution, providing the corresponding products in moderate to good yields (up to 99%) with up to 96:4 er. Experimental and computational mechanistic studies using DFT calculation and pseudotransition state (pseudo-TS) conformational search afforded a TS model accounting for the origin of the stereoselectivity. The model suggested π-stacking and H-bonding interactions play essential roles in stabilizing the TS structures.
Yamamoto, Eiji,Wakafuji, Kodai,Furutachi, Yuho,Kobayashi, Kaoru,Kamachi, Takashi,Tokunaga, Makoto
p. 5708 - 5713
(2018/05/30)

Target autophagy agonist and application thereof in neurodegenerative disease treating medicine
The invention relates to a target autophagy agonist and application thereof in a neurodegenerative disease treating medicine and belongs to the technical field of neurodegenerative disease resisting pharmacy. The invention aims at providing a compound serving as ULK1 agonist. The compound is prepared from following shown compound or pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof can serve as the ULK1 agonist and has certain neurodegenerative disease resisting activity.
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Paragraph 0051; 0053; 0054; 0055

(2017/07/20)

New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
p. 2127 - 2132
(2017/10/31)

2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS DUAL INHIBITORS OF PDK1/AURA
The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) in the treatment of pathologies which require a dual inhibitor of PDK1/AurA enzymes such as for instance tumours, particularly glioblastoma.
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Page/Page column 19-20; 29

(2018/01/15)

A chiral 2-phenyl pyrrolidine synthetic method
The invention discloses a synthetic method of chiral 2-phenylpyrrolidine. The synthetic method comprises the following steps: (1) butoxycarbonyl protective reaction: carrying out reaction on chiral 2-amino-phenylacetic acid and di-tert-butyl dicarbonate to obtain chiral 2-( butoxycarbonyl amino)-2-phenylacetic acid; (2) condensation and reduction reaction: carrying out condensation on the chiral 2-(butoxycarbonyl amino)-2-phenylacetic acid and 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, and carrying out reduction by virtue of sodium borohydride to obtain chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate; (3) de-protection and heating ring closure reaction: carrying out de-protection and heating ring closure reaction on the chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate to obtain chiral 5-phenylpyrrolidine-2-ketone; and (4) reduction reaction: reducing the chiral 5-phenylpyrrolidine-2-ketone by virtue of lithium aluminium hydride to obtain the chiral 2-phenylpyrrolidine. The synthetic method is simple in operation, high in yield and cheap and easily acquired in raw materials and is suitable for industrial production.
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Paragraph 0041; 0042

(2017/02/02)

Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma
The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the master kinase of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds were synthesised and a tandem application of docking and Molecular Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower IC50 (IC50 Combining double low line 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction.
Sestito, Simona,Daniele, Simona,Nesi, Giulia,Zappelli, Elisa,Di Maio, Danilo,Marinelli, Luciana,Digiacomo, Maria,Lapucci, Annalina,Martini, Claudia,Novellino, Ettore,Rapposelli, Simona
supporting information
p. 47 - 63
(2016/05/09)

Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine
Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I+ under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.
Li, Jing,Lear, Martin J.,Kwon, Eunsang,Hayashi, Yujiro
p. 5538 - 5542
(2016/04/20)

2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS INHIBITORS OF PDK1
The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) and new 2-oxo-1,2-dihydropyridine-3-carboxamide compounds of Formula (II) in the treatment of pathologies which require an inhibitor of PDK1 enzyme such as diabetes, neurodegenerative diseases such as Alzheimer's and Prion Diseases, and tumours such as breast, and pancreatic cancers and glioblastoma, particularly glioblastoma.
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Page/Page column 21; 22; 23

(2016/12/26)

Enantiomeric discrimination of α-hydroxy acids and N-Ts-α-amino acids by1H NMR spectroscopy
A new kind of chiral compounds with multiple amino, amido and phenolic hydroxy groups has been synthesized from D-phenylalanine and D-phenylglycine, respectively. The enantiomeric discriminations of α-hydroxy acids and N-Ts-α-amino acids have been finished in the presence of the above chiral compounds as chiral solvating agents by1H NMR spectroscopy. The results show that the chiral compounds are highly effective and practical chiral solvating agents towards α-hydroxy acids and N-Ts-α-amino acids.
Gao, Guangpeng,Lv, Caixia,Li, Qiuju,Ai, Lin,Zhang, Jiaxin
p. 6742 - 6746
(2016/09/09)

HETEROARYL DERIVATIVES
Compounds of formula (I) described herein are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.
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Paragraph 0502; 0503; 0504

(2015/06/17)

HETEROARYL DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES
The invention relates to novel compounds of formula (I) which are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 116; 117

(2015/06/18)

Dual Catalytic Decarboxylative Allylations of α-Amino Acids and Their Divergent Mechanisms
The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.
Lang, Simon B.,O'Nele, Kathryn M.,Douglas, Justin T.,Tunge, Jon A.
supporting information
p. 18589 - 18593
(2016/01/25)

Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine
The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.
Li, Jing,Lear, Martin J.,Kawamoto, Yuya,Umemiya, Shigenobu,Wong, Alice R.,Kwon, Eunsang,Sato, Itaru,Hayashi, Yujiro
p. 12986 - 12990
(2015/11/02)

PHENYLETHYLPYRIDINE DERIVATIVES AS PDE4-INHIBITORS
The invention relates to novel compounds which are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 69; 70

(2014/06/24)

NOVEL COMPOUNDS
Compounds of formula (I) defined herein are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction.
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Paragraph 0431 - 0433

(2014/06/23)

Synthesis and biological evaluation of new pleuromutilin derivatives as antibacterial agents
Several pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant S. aureus, methicillin-resistant S. epidermidis, S. aureus, S. epidermidis, E. coli, and B. cereus were tested by the agar dilution method and Oxford cup assay. All the screened compounds displayed potent activity. Compound 6d was the most active antibacterial agent because of its lowest MIC value and largest inhibition zone. Docking experiments were performed to understand the possible mode of the interactions between the derivatives and 50S ribosomal subunit. Moreover, the absorption, distribution, metabolism, excretion and toxicity properties of the synthesized compounds were analyzed after prediction using the Advanced Chemistry Development/Percepta Platform available online.
Shang, Ruo-Feng,Wang, Guan-Hua,Xu, Xi-Ming,Liu, Si-Jie,Zhang, Chao,Yi, Yun-Peng,Liang, Jian-Ping,Liu, Yu
p. 19050 - 19065
(2015/02/05)

ANTI-PCSK9 COMPOUNDS AND METHODS FOR THE TREATMENT AND/OR PREVENTION OF CARDIOVASCULAR DISEASES
Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.
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Page/Page column 32

(2014/10/04)

Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: Potent inhibitors of R5 HIV-1 replication
The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
Skerlj, Renato,Bridger, Gary,Zhou, Yuanxi,Bourque, Elyse,McEachern, Ernest,Metz, Markus,Harwig, Curtis,Li, Tong-Shuang,Yang, Wen,Bogucki, David,Zhu, Yongbao,Langille, Jonathan,Veale, Duane,Ba, Tuya,Bey, Michael,Baird, Ian,Kaller, Alan,Krumpak, Maria,Leitch, David,Satori, Michael,Vocadlo, Krystyna,Guay, Danielle,Nan, Susan,Yee, Helen,Crawford, Jason,Chen, Gang,Wilson, Trevor,Carpenter, Bryon,Gauthier, David,MacFarland, Ron,Mosi, Renee,Bodart, Veronique,Wong, Rebecca,Fricker, Simon,Schols, Dominique
supporting information
p. 8049 - 8065
(2013/11/06)

One-step synthesis of racemic α-amino acids from aldehydes, amine components, and gaseous CO2 by the aid of a bismetal reagent
α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid can be divided into three basic components: an aldehyde, an amine, and carbon dioxide (CO2). We report herein that a one-step synthesis of α-amino acids has been successfully achieved from these three basic and inexpensive chemicals with a single operation, in which the mixture of an aldehyde, a sulfonamide, and gaseous CO2 was heated at 100 °C in the presence of Bu3Sn-SnBu3 and CsF. In this one-pot sequential protocol, two important intermediates (imine and α-amino stannane) are involved and the stannyl anion generated in situ plays a crucial role, particularly for the efficient stannylation of the imine in the presence of proton sources and for promoting retrostannylation of the undesired α-alkoxy stannane owing to its high stability and tolerance of the presence of proton sources. This methodology enabled the synthesis of a wide range of racemic arylglycine derivatives in high yields. Go retro! α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid is retrosynthesized to an aldehyde, an amine, and carbon dioxide. A one-step synthesis of α-amin Copyright
Mita, Tsuyoshi,Higuchi, Yuki,Sato, Yoshihiro
p. 1123 - 1128
(2013/02/23)

Synthesis and antibacterial evaluation of novel pleuromutilin derivatives
A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions. Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay. Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents.
Shang, Ruofeng,Liu, Yu,Xin, Zhijun,Guo, Wenzhu,Guo, Zhiting,Hao, Baocheng,Jianping, Liang
p. 231 - 238
(2013/07/27)

GLYCINE DERIVATIVES AND THEIR USE AS MUSCARINIC RECEPTOR ANTAGONISTS
The present invention relates to alkaloid aminoester derivatives acting as muscarinic receptor antagonists, processes for their preparation, compositions comprising them and therapeutic uses thereof.
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Page/Page column 31

(2012/06/15)

GLYCINE DERIVATIVES AND MEDICINAL COMPOSITIONS THEREOF
Alkaloid aminoester derivatives according to formula (I) and (VI) act as muscarinic receptor antagonists.
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Page/Page column 11

(2012/06/16)

Highly enantioselective reduction of β-amino nitroolefins with a simple n-sulfinyl urea as bifunctional catalyst
Simple but effective: A structurally simple N-sulfinyl urea was found to be a highly efficient bifunctional catalyst, which allows for the development of a novel pathway for the construction of chiral β-amino nitroalkanes through enantioselective reduction of β-amino nitroolefins by trichlorosilane. High yields and excellent enantioselectivities were obtained for a broad range of β-arylamino nitroolefin substrates (see scheme). Copyright
Liu, Xiang-Wei,Yan, Yan,Wang, Yong-Qiang,Wang, Chao,Sun, Jian
p. 9204 - 9207
(2012/08/27)

One-pot synthesis of α-amino acids from CO2 using a bismetal reagent with Si-B bond
In the presence of 1.1 equiv of PhMe2Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH·H2O, precursors of N-Boc-imines can be converted into the corresponding α-aryl or α-alkenyl glycine derivatives under gaseous CO2 in moderate-to-high yields with a single operation. α-Isobutenyl glycine thus obtained can be further derivatized into various types of α-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.
Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
supporting information
p. 6202 - 6205
(2013/02/23)

Synthesis of arylglycine and mandelic acid derivatives through carboxylations of α-amido and α-acetoxy stannanes with carbon dioxide
Incorporation reactions of carbon dioxide (CO2) with N-Boc-α-amido and α-acetoxy stannanes were developed using CsF as a mild tin activator. Monoprotected α-amido stannanes could be used, and the corresponding arylglycine derivatives were obtained in moderate-to-high yields under 1 MPa (10 atm) of CO2 pressure. α-Acetoxy stannanes also underwent carboxylation to afford mandelic acid derivatives in excellent yields under ambient CO2 pressure. Both transformations enabled the synthesis of α-tertiary and α-quaternary carboxylic acid derivatives. In addition, the chirality of (S)-N-tert-butylsulfonyl-α- amido stannanes was transferred with up to 90% inversion of configuration at 100 °C.
Mita, Tsuyoshi,Sugawara, Masumi,Hasegawa, Hiroyuki,Sato, Yoshihiro
experimental part
p. 2159 - 2168
(2012/06/01)

Synthetic approach to gain insight into antigenic determinants of cephalosporins: In vitro studies of chemical structure-IgE molecular recognition relationships
Cephalosporins, after penicillins, are the most widely used antibacterial agents in infectious diseases and the cause of adverse immune reactions in the world. Whether a patient with a suspected allergy to a β-lactam can safely take a cephalosporin is often a matter of debate. However, there are no tests with enough sensitivity to detect allergy to cephalosporins. Understanding the way in which the drug metabolizes after protein conjugation is important if we are to make advances in the diagnosis of clinical allergy. Structural studies of cephalosporin-protein adducts have never been addressed successfully and are difficult to investigate. Our approach to determine the requirements involved in antigenic determinant structures consisted of designing and synthesizing a proposed skeleton that remains linked to the carrier protein after chemical degradation in cephalosporin conjugated to carrier proteins. In this study, a series of proposed epitopes were efficiently synthesized following a versatile methodology, involving the condensation of the R1 acyl side chains of native cephalosporins, with the nuclear fragment structures (derived from amino acids or other aminofunctionalized molecules). The final well-defined structures 1-4 (a-f), representing a fragment from the proposed cephalosporin-Lys(protein) adduct intermediate, consist of closely related low-molecular-weight molecules, differing only in the functional group at C-3 and the R1 side chains. They were assessed with sera from patients allergic to cephalosporins to study structure-IgE molecular recognition relationships. These IgE showed an enhanced recognition to proposed new skeleton epitopes with adequate functionality at C-3, with the specifities mainly related to the R1 acyl side chain. Thus, this study led us to refine the model haptenic structures of cephalosporins and gain insight into the chemical mechanism of epitope formation.
Montanez, Maria Isabel,Mayorga, Cristobalina,Torres, Maria Jose,Ariza, Adriana,Blanca, Miguel,Perez-Inestrosa, Ezequiel
experimental part
p. 706 - 717
(2012/03/11)

Discovery of small molecules that enhance astrocyte differentiation in rat fetal neural stem cells
1,3,4-Oxadiazole derivatives were found to enhance astrocyte differentiation in rat fetal neural stem cells (NSCs). Differentiation activity was assessed by immunocytochemistry and analysis of mRNA expression of astrocyte markers, GFAP and S100. Compounds 7 and 8 showed approximately a two-fold increase in astrocyte differentiation without engagement of neuronal differentiation and detectable cytotoxicity.
Chang, Dong Jo,Jeong, Mi Young,Song, Jiho,Jin, Chang Yun,Suh, Young-Ger,Kim, Hyun-Jung,Min, Kyung Hoon
supporting information; scheme or table
p. 7050 - 7053
(2012/01/13)

One-pot synthesis of α-amino acids from imines through CO2 incorporation: An alternative method for strecker synthesis
Itas a gas: A novel one-pot process for the synthesis of α-amino acids from imine equivalents using CO2 gas as a carbon source has been developed. This reaction was made possible by the reagent combination of TMSSnBu3 and CsF (see scheme). Three successive reactions (imine formation, stannylation, and carboxylation) proceeded in the same flask under these conditions to give products in up to 79 % yield. Boc=tert-butoxycarbonyl, TMS=trimethylsilyl.
Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
p. 1393 - 1396
(2011/04/22)

Highly enantioselective fluorescent recognition of amino acid derivatives by unsymmetrical salan sensors
Novel unsymmetrical salan fluorescent sensors 2a and 2b have been designed and synthesized. The chiral recognition of N-Boc-protected amino acids by 2a and 2b has been investigated. Sensor 2a possesses higher sensitivity and enantioselectivity than sensor 2b does. Job analysis and nonlinear regression results show that 2a can form a 1:1 stoichiometric complex with a N-Boc-protected amino acid. The obtained response selectivities and the association constants indicate that 2a is a highly enantioselective and sensitive fluorescent sensor toward N-Boc-protected amino acids.
Yang, Xia,Shen, Kang,Liu, Xuechao,Zhu, Chengjian,Cheng, Yixiang
scheme or table
p. 4611 - 4614
(2011/10/01)

Enantiomeric resolution of α-amino acid derivatives on two diastereomeric chiral stationary phases based on chiral crown ethers incorporating two different chiral units
Two diastereomeric chiral stationary phases (CSPs) were applied to the liquid chromatographic resolution of various racemic a-amino methyl esters, α-amino N,N-diethylamides and α-amino N-propylamides. The CSP incorporating (R)-3,3' -diphenyl-1,1' -binaphtyl and (R,R)-tartaric acid unit as chiral barriers did not show any chiral recognition. In contrast, the CSP incorporating (R)-3,3'-diphenyl-1,1'-binaphtyl and (S,S)-tartaric acid unit as chiral barriers was found to show excellent chiral recognition especially for the two enantiomers of a-amino N-propylamides. Some of a-amino methyl esters and α-amino N,N-diethylamides were also resolved on the CSP incorporating (R)-3,3'-diphenyl-1,1'-binaphtyl and (S,S)-tartaric acid unit. From these results it was concluded that the two chiral units composing the diastereomeric CSPs can show "matched" or "mismatched" effect on the chiral recognition according to their absolute stereochemistry.
Kim, Hee Jin,Choi, Hee Jung,Cho, Yoon Jae,Hyun, Myung Ho
body text
p. 1551 - 1554
(2010/10/20)

COMPOUNDS HAVING ACTIVITY IN INCREASING ION TRANSPORT BY MUTANT-CFTR AND USES THEREOF
The invention provides compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The compositions pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The compositions and pharmaceutical preparations of the invention may comprise one or more phenylglycine-containing compounds of the invention, or an analog or derivative thereof
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(2009/05/28)

1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity
A number of 1-propargyl-1,8-naphthyridine-3-carboxamide derivatives (15-35) have been synthesized and screened for their in vitro cytotoxicity and anti-inflammatory activity. Compounds 22, 31 and 34 have shown high cytotoxicity against a number of cancer cell lines, while compound 24 showed significant anti-inflammatory activity.
Kumar, Vivek,Jaggi, Manu,Singh, Anu T.,Madaan, Alka,Sanna, Vinod,Singh, Pratibha,Sharma, Pramod K.,Irchhaiya, Raghuveer,Burman, Anand C.
experimental part
p. 3356 - 3362
(2009/10/23)

A practical synthesis of optically active arylglycines via catalytic asymmetric Strecker reaction
A practical procedure for catalytic asymmetric synthesis of optically active arylglycine derivatives via optically active α-aminonitriles has been developed. The N-benzhydryl α-arylaminonitrile intermediates were prepared in excellent yield (89-99%) and enantiomeric purity (96 to >98% ee) by enantioselective cyanation of aldimines with TMSCN/iPrOH in the presence of 2.5 mol % of an easily prepared Ti/chiral amino alcohol complex at 0 °C, without requiring slow addition of the cyanating agent. The easily racemized α-aminonitrile intermediates were efficiently hydrolyzed by an aqueous HCl/TFA mixture to give the arylglycine derivatives in good yield (60-92%) and moderate to excellent enantiomeric purity (85-98% ee).
Banphavichit, Vorawit,Mansawat, Woraluk,Bhanthumnavin, Worawan,Vilaivan, Tirayut
experimental part
p. 5849 - 5854
(2009/12/01)

Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure
Structure-activity relationships (SAR) of 1 against HCV NS5B polymerase were described. SAR explorations and further structure-based design led to the identifications of 2 and 3 as novel HCV NS5B inhibitors. X-ray structure of 3 in complex with NS5B polymerase was obtained at a resolution of 2.2 A, and confirmed the design.
Yan, Shunqi,Larson, Gary,Wu, Jim Z.,Appleby, Todd,Ding, Yili,Hamatake, Robert,Hong, Zhi,Yao, Nanhua
p. 63 - 67
(2007/10/03)

Iridium(I)-catalyzed regio- and enantioselective allylic amidation
Ir(I)-catalyzed intermolecular allylic amidation of ethyl allyl carbonates with soft nitrogen nucleophiles under completely 'salt-free' conditions is described. A combination of [Ir(COD)Cl]2, a chiral phosphoramidite ligand L*, and DBU as a base in THF effects the reaction. The reaction appears to be quite general, accommodating a wide variety of R-groups and soft nitrogen nucleophiles, and proceeds with excellent regio- and enantioselectivities to afford the branched N-protected allylic amines. The developed reaction was conveniently utilized in the asymmetric synthesis of N-Boc protected α- and β-amino acids as well as (-)-cytoxazone.
Singh, Om V.,Han, Hyunsoo
p. 7094 - 7098
(2008/03/11)

Enantioselective aza-Henry reactions assisted by ZnII and N-methylephedrine
(Chemical Equation Presented) Hooray aza-Henry! A combination of zinc triflate, an amine base, and (-)-N-methylephedrine (NME), which can be easily recovered and reused, leads to high enantioselectivities in the aza-Henry reaction of N-Boc-protected aldimines and nitromethane (see scheme; Boc = tert-butyloxycarbonyl).
Palomo, Claudio,Oiarbide, Mikel,Halder, Rajkumar,Laso, Antonio,Lopez, Rosa
p. 117 - 120
(2007/10/03)

Bifunctional-thiourea-catalyzed diastereo- And enantioselective Aza-Henry reaction
Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-β-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the prod ucts, that is, the reaction of N-Bocimines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.
Xu, Xuenong,Furukawa, Tomihiro,Okino, Tomotaka,Miyabe, Hideto,Takemoto, Yoshiji
p. 466 - 476
(2008/09/20)

METHOD FOR PRODUCING SOLUTION CONTAINING N-t-BUTYLOXYCARBONYLAMINO ACID
PROBLEM TO BE SOLVED: To provide a method for producing a solution containing an N-t-butyloxycarbonylamino acid (BOCA) with which the production efficiency is good. SOLUTION: The method for producing the solution containing the BOCA comprises the following steps (a) to (c). (a) A step of reacting di-t-butyl dicarbonate with an amino acid in an amount of equivalent based on the carbonate in the presence of an organic solvent immiscible with water, a base and water and affording a reaction mixture containing a salt of the BOCA, (b) a step of adding an acid to the reaction mixture, producing the free BOCA and extracting the produced BOCA with the organic solvent immiscible with water and (c) a step of separating an organic phase containing the BOCA obtained in the step (b) and the organic solvent immiscible with water from an aqueous phase containing a salt produced by a neutralizing reaction of the acid with the base.
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(2008/06/13)

Asymmetric allylboration of α,β-enals as a surrogate for the enantioselective synthesis of allylic amines and α-amino acids
(Chemical Equation Presented) Optically pure allylic amines have been synthesized from α,β-unsaturated aldehydes via allylboration with (-)-B-allyldiisopinocampheylborane, followed by Overman rearrangement. By incorporating crotyl and alkoxyallylboration, functionalization at δ-position was readily accomplished. By applying this methodology, the synthesis of several chiral α-amino acids has been achieved.
Ramachandran, P. Veeraraghavan,Burghardt, Thomas E.,Reddy, M. Venkat Ram
p. 2329 - 2331
(2007/10/03)

Chiral gelators constructed from 11-aminoundecanoic (AUDA), lauric and amino acid units. Synthesis, gelling properties and preferred gelation of racemates vs. the pure enantiomers
A new class of efficient low molecular weight gelator molecules has been designed by combining 11-aminoundecanoic acid (AUDA), lauric acid and aromatic and aliphatic amino acid units in the same molecule. This yields a special class of fatty acid amphiphiles with core chiral centres and hydrogen bonding sites. Some of the compounds with terminal carboxylic acid and sodium carboxylate functions exhibited ambidextrous gelation properties, being able to form gels both with highly polar solvents (water, DMSO) and also with highly lipophilic solvents, including two hydrocarbon fuels. At variance with several recent observations that the enantiomers are generally more efficient gelators than the corresponding racemates, some of the racemic gelators prepared in this work were found to be capable of gelling up to 16 times larger volumes of certain solvents than the pure enantiomers. Temperature-dependent FTIR and 1H NMR studies of the gels formed by derivatives with terminal carboxylic acid groups and lipophilic solvents revealed that intermolecular hydrogen bonding between amidic and carboxylic acid units was involved in the self-assembly of gel aggregates. Additional strong stabilization of the aggregates was observed in the gelators possessing terminal sodium carboxylate groups, and this was attributed to the electrostatic and ion-dipole interactions between the sodium carboxylate groups. This additional stabilization appears to be responsible for considerably higher thermal stability of the latter gels in relation to those formed by gelators with terminal carboxylic acid groups. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
Caplar, Vesna,Zinic, Mladen,Pozzo, Jean-Luc,Fages, Frederic,Mieden-Gundert, Gudrun,Voegtle, Fritz
p. 4048 - 4059
(2007/10/03)

ARYLGLYCINE DERIVATIVES AND THEIR USE AS GLYCINE TRANSPORT INHIBITORS
The present invention relates to compounds of Formula (I), and salts solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing said compounds and methods of treating neurological, neuropsychiatric, and gastrointestinal disorders using said compounds.
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(2010/02/06)